TW201219384A - Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings, wherein the pharmaceutical composition contains (3aS, 5s, 6aR)-5-(2-((2S, 4S)-2-cyano-4-fluoropyrrolidine-1-yl)-2-oxo-ethylamino)-N, N, 5-trimethyl-hexahydro-cyclopenta[C]pyrrole-2(1H)-carboxamide or its pharmaceutically acceptable salts and rosiglitazone or pioglitazone or their pharmaceutically acceptable salts, preparation method thereof and a method of treating 2 type diabetes in mammals including human beings with the composition.

Description

201219384 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a pharmaceutical composition for treating type 2 diabetes in a mammal including humans, particularly containing rosiglitazone or pioglitaline or their pharmaceutically acceptable Salt with (3as,5s,6aR)-5-(2-((2S,js)_2-cyano-4-fluoro-pyrrolidine~1-yl)-2-oxoethylamino)-indole, ν a pharmaceutical composition of 5, dimethyl-hydrogencyclopenta[C]pyrrole-2(1Η)-guanamine or a pharmaceutically acceptable salt thereof, in a fixed dose combination, for preparing the pharmaceutical composition : and the use of the pharmaceutical composition for the treatment of type 2 diabetes in mammals including humans. [Prior Art] Type 2 diabetes is a chronic and progressive disease caused by the complex pathophysiology of dual endocrine defects involving insulin resistance and attenuation of insulin. The treatment of type 2 diabetes generally begins with diet and exercise, followed by oral monotherapy for antidiabetic drugs. For many patients, this regimen does not adequately control blood glucose during long-term treatment, which results in the need for combination therapy within a few years after the diagnosis. However, the co-prescription of two or more anti-diabetic drugs is for many patients to use: a complex and difficult treatment regimen. Combining two or more anti-sugar agents into a single formulation provides a possible means of delivering a combination therapy that does not increase the patient's daily sex. Institutional Alienation The dipeptidyl peptidase_IV (DPP_IV) inhibitor represents a class of abandonment reagents developed for the treatment or improvement of i-glycan control in patients with a second Weiwei disease. The drug used in the treatment of type 2 diabetes in current clinical trials is 3 95021 201219384 1^-〇43Buvidadine (^^-237), 5&乂3, 11?1^11^1^-47718), P93/01 (Prosidon), SYR322 (Takeda), GSK823093, Roche0730699, TS021 (Taisho), E3024 (Eisai) and PHX-1149 (Phenomix). For example, it has been found that oral administration of vildagliptin to a type 2 diabetic patient can reduce the fasting glucose and postprandial glucose deviation associated with a significantly reduced HbAIC level. For a review of the use of DDP-IV in the treatment of type 2 diabetes, see the following publications: (1) H.-U. Demuth et al., "Type 2diabetes-Theraphy with dipeptidyl peptidase IV inhibit0rs", Biochim. Biophvs. Acta. 1751: 33-44 (2005) and (2) K· Augustyns et al., “Inhibitors of proline-specific dipeptidyl peptidases: DPP4 inhibitors as a novel approach for the treatment of Type 2 diabetes” , Expert Opin. Ther. Patants, 15:1387 -1407 (2005). Some DPP-IV inhibitors have been disclosed (US5462928, US5543396 > W09515309 > W02003004498 'W02003082817 > W02004032836, W02004085661), wherein the DPP-IV inhibitor HAF-237 produced by Novartis Company shows good DPP-IV inhibition. Activity and selectivity, and was launched in 2007. ,

LAF-237 In order to administer a PPAR anti-diabetic agent, particularly glitazone, to an adult 201219384 diabetic patient (body weight: 5 〇 kg), for example, the daily dose is usually 〇 to mg', preferably 0.1 to 500 mg. The dosage is administered daily ~ times, especially when β glitazone is used as the insulin sensitizing sword, and the daily dose of gueglitazone hydrochloride is usually 7.5 to 60 mg, preferably ^ to 45 mg. When rosiglitazone (or maleate) is used as an insulin sensitizer, the daily dose of rosiglirel is usually from 1 to 12 nig, preferably 2 mg of 12 mg 〇 glitazone is preferably pioglitazone. Pioglitazone hydrochloride or rosiglitazone (or its maleate) is particularly preferably the same as the salt. Pharmaceutical dosage forms of a combination of an anti-diabetic agent and a thiazolidine dione derivative have been proposed in the art. For example, ep〇_751 teaches a pharmaceutical composition comprising a guar-based sensitivity enhancer which is a burnt-offering compound in combination with other anti-diabetic agents. More particularly, Ep 749 751 teaches that a preferred tensin sensitivity enhancer is π-bitagidin, which can be combined with other anti-diabetic agents such as rogglirel, phenformin or butyl double pulse, and These drugs can be combined (mixed and/or coated) with conventional excipients to provide a taste mask or hold, 'other release. Another example of a combination of an antidiabetic agent and a bismuth sulfonium diketone derivative is U.S. Patent No. 6,011, _, which teaches a sustained release form, such as an osmotic pump or a skin patch containing pioglitazone or troglita A single pharmaceutical composition of rosiglitazone or pioglitazone. Other combinations of antidiabetic agents and thiazolidinedione derivatives can be found in U.S. Patent No.

6' 524' 621; 6, 475, 521; 6, 451, 342 and 6, 153, 632 and pCT patent application WO 0 1/3 594, which are incorporated herein by reference. SUMMARY OF THE INVENTION 95021 201219384 (3aS, 5s, 6aR)-5-(2-((2S, 4S)_2-cyano)) 2-oxoethylamino)-N,N,5- Tridecyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carbenamide is Compound A.

Compound A Compound A or its salt inhibited DPP-IV activity longer than LAF-237 ® and had a greater inhibitory intensity than LAF-237. Through experimental research, the inventors have surprisingly found that the compound efficacy of Compound A or its salt and rosiglitazone or pioglitazone or a salt thereof is significantly higher than that of either component alone, especially when 'Rogler' The compounding ratio of the ketone or the salt thereof and the compound A or the salt thereof is 1: 6.25 to 1:75, and the compounding ratio of the pioglitazone or the salt thereof and the compound A or the salt thereof is from 1:3 to 1:50, and the effect is better. . Therefore, a composition composed of the compound A or a salt thereof and rosiglitazone or a salt thereof, the composition of the compound A or a salt thereof and the pioglitazone or a salt thereof is clinically significant. The present invention provides a pharmaceutical composition of a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and rosiglitazone or pioglitazone or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention provides that the two active pharmaceutical ingredients are immediate or slow release. The pharmaceutical composition of the present invention is in the form of a tablet, and particularly a coated tablet, and may be other oral dosage forms such as a capsule. One aspect of the invention relates to a dosage form for the pharmaceutical administration of a fixed dose combination of Compound A or a drug thereof 95021 201219384 • a scientifically acceptable salt and a roberger steel or a mouth of gliardine or a salt thereof. The dosage form can be a two solid = and includes tablets, capsules, sachets and the like. Specific: The dosage form relates to containing Compound A or a pharmaceutically acceptable salt thereof and

A tablet of the amount of W of ketone or oral glibenclamide or a pharmaceutically acceptable salt thereof. W, and δ, this month also provides a method for preparing a solid of a compound or a salt thereof and rosiglitazone or strontium chloride or a salt thereof by a dry or wet treatment method. Dry processing methods include dry compression and dry granulation' and wet processing methods include wet granulation. Another aspect of the invention provides the use of a pharmaceutical composition of the invention for the treatment of Type 2 diabetes in a mammal, including a human, comprising administering to the subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the invention. In a specific embodiment of the present invention, the pharmaceutical composition comprises (1) a substance A or a pharmaceutically acceptable salt thereof, which is a first active drug into a sputum '(2) rosiglitazone or a ketal or a salt thereof , is the second active drug f component; and (3) the drug or help (four). In the specific pertinent scheme of this aspect (4), the pharmaceutical composition may further contain one or more kinds of excipients, and the excipients may be derived from a variety or a multi-wei agent (binding agent); , one or more surfactants or wetting agents; one or more disintegrants; and one or more antioxidants. Compound A pharmaceutically acceptable guanidine, rosiglitazone or pioglitazone: including but not limited to 'p-toluene lye salt, wei salt, hydrochloride salt, sulfuric acid salt, nitrate salt, hydrogen hydride acid salt, continuation Acid salt, maleate salt, tartrate salt, 95021 7 201219384 amber (10) salt, acetate, trifluoroacetate, fumarate, citric acid, citrate, benzoate, benzene f , Cai Citrate, lactate. The compound A or a salt thereof incorporated in the pharmaceutical composition of the present invention is administered in a daily dose of 25 g to 300 mg per person. Preferably, the compound A or a salt thereof is administered in a dose of from milligrams to 200 milligrams per person per dose. The individual dose per person per day is 25, 5 〇, 75, qing, 15 (), normi gram of Compound A or its salt. The daily dose of Roglin left or its salt incorporated into the fixed dose combination of the present invention is from 1 mg to 12 mg per day, and the individual daily doses are 2, 4, 8, 10 and 12 mg per person. 'Pioglitazone or its salt per person per dose is 7 5 vouchers $ Lisie grams to 60 mg, individual daily doses are 7. 5, 15, 30, 45 and π 客六la · # U Mg. These daily doses of rosiglitazone or pioglitazone or its salts represent dosages approved for commercial treatment of human type 2 diabetes in China and/or the United States. In the fixed dose combination of the present invention, the specific embodiment of the daily dose of Compound A or its salt and rosiglitazone or sputum or their salt is as follows: Becky Compound A or its salt ) 25 ' 50,75,100,150,200, 250 , 300 rosiglitazone or a salt thereof (mgM, 2, 4, 8, ΐ2 吼glipizide or a salt thereof (mgn.5, l5, 3 〇, 45,6{) Any therapeutically effective amount of a therapeutically effective amount of any of the therapeutically effective amounts of rotastatin or a salt thereof, such as 95021 201219384 50+2, 50+4,100+ 2,100+4 or 50+7. 5,50+15,50+30,50+45, 75+7. 5,75+15,100+30,100+45, etc. In the pharmaceutical composition of the present invention The two active pharmaceutical ingredients can be in four release forms: their salt is released immediately and the release is immediate release of the slow release ingredient: the compound guanidine or its salt rosiglitazone or tiglitazone or immediate release immediate release slow release slow release The pharmaceutical composition of the invention is prepared by a wet method or a dry method. In one embodiment, the pharmaceutical composition is treated by a wet method. The preparation is carried out. In one class of this embodiment, the pharmaceutical composition is prepared by a wet granulation process. In wet granulation, high shear granulation or fluidized bed granulation can be applied. In one embodiment The use of fluidized bed granulation has the advantage of making the tablet have a higher radial strength. The pharmaceutical composition obtained by dry or wet processing can be compressed into tablets, packaged or metered into sachets. The lubricant contains one or more lubricants or glidants. Examples of lubricants include magnesium stearate, stearic acid, 1 bow, stearic acid, sodium stearyl fumarate, hydrogenated castor oil or mixtures thereof. The lubricant is magnesium stearate or sodium stearyl fumarate or a mixture thereof. Examples of the glidant include colloidal cerium oxide, calcium phosphate, magnesium citrate and talc. The pharmaceutical composition of the present invention optionally contains one or A variety of binders. Embodiments of the binder include hydroxypropyl cellulose (HPC), hydroxypropyl decyl cellulose (HMPC), hydroxyethyl cellulose, starch 15 〇〇, polyvinyl pyrrole 9 95021 201219384 fine ((4) Side side. The preferred ageing polyglycol is sulphur ketone. The pharmaceutical composition of the present invention may optionally contain one or more diluents. Examples of the diluent include mannitol, sorbitol, and Wei Erji. Hydrate, microcrystalline cellulose and powdered cellulose.

Crystal cellulose. Microcrystalline cellulose can be obtained from several suppliers including Avicel PH 1〇1, Avicel pH PH 103, Avicel PH 105 and Avicel PH 200 manufactured by (10) Corporation. The pharmaceutical composition of the present invention may further optionally contain a disintegrating agent. The collapse can be several modified temple powders, modified cellulose polymers or two-types of poly-decanoic acid such as cross-linking "based cellulose sodium, acetyl alcohol, and potalalin potassium: hydroxydecyl cellulose calcium (4) Calcium). In one implementation, the disintegrant is crosslinked via cellulose. Cross-linked shrimp

Type A is commercially available under the trade name "Ac-di-sol," F. The pharmaceutical composition of the present invention may optionally contain a seed or an ionic wetting agent. The surfactant may be an anion, sodium sulphate, The twelve-anionic surfactant includes lauryl: r::r nano. Cationic surfactant package == poly 2 = γτ includes glycerol monooleate, and the solution includes poloxamer, polyoxyethylene dilute, material Sesame oil and polystyrene stearic acid. Antioxidant can be added to the preparation as needed to give it stability. The antioxidant is selected from tocopherol, τ-tocopherol, and monotocopherol. Tocopherol enriched with extracts of natural origin, ascorbic acid and its sodium or calcium salts, ascorbate palmitate, propyl gallate, octyl citrate, lauryl citrate, butylated hydroxy group Stupid and butylated hydroxyphenyl ether (ΒΗΑ). In one embodiment, the antioxidant is or bha. A preferred dosage form of the pharmaceutical composition of the invention is a tablet prepared via a compression process. Hydroxypropyl fiber A mixture of hydroxypropyl hydrazine and hydroxypropyl hydrazine is coated with a film of '5 hai. The mixture contains dioxin and / geqi 0 his coloring agent 'such as iron oxide, dye and lake; polyvinyl alcohol (pVA) II a mixture of polyethylene glycol (PEG) containing titanium dioxide and/or other pigmented colors such as iron oxide, dyes and lakes; or any other suitable immediate release coating. The coating provides a taste mask to the final tablet. And additional stability. Commercially available coatings are Opadry® supplied by Colorcon to formulate powders. Finally, 'if needed' can be added with sweeteners and/or flavoring agents. • Rogge column of the present invention The ketone or pioglitazone or a salt thereof may be either immediate or slow release, and the compound A or its salt may be either immediate or slow release. The pharmaceutical tablet composition of the present invention may further contain one or more additional Formulation ingredients selected from excipients known in the art of various pharmaceutical preparations. Depending on the desired properties of the pharmaceutical combination, based on their known use in the preparation of tablet compositions' may be alone or A combination of any of the ingredients is included. This ingredient includes, but is not limited to, diluents, compression aids, glidants, disintegrants, lubricants, perfumes, flavoring agents, sweeteners, and preservatives. 95021 11 201219384 Used herein The term "tablet" is intended to include compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or not. Substances that can be used for coating include propylcellulose, propylmethylcellulose, titanium dioxide, talc, sweetness. Agents, Colorants, and Flavoring Agents. The present invention also provides a method of treating a mammal, including human type 2 diabetes, a therapeutically effective amount of a fixed dose combination pharmaceutical composition of the present invention via oral administration of a subject in need of such treatment. In the solution, the subject in need of the treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet or a capsule. Pharmaceutical compositions containing a fixed dose combination can be administered once per day (QD), twice daily (BID) or three times daily (TID). Method for synthesizing the compound A of the present invention (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxoethylamine Method for synthesizing hydrazine, hydrazine, 5-trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-decylamine (Compound A) according to the method described in Example 18 of PCT/CN2008/071014 Preparation, therefore, the disclosure is incorporated herein by reference. [Embodiment] The following examples further describe and illustrate embodiments within the scope of the invention. The examples and the test examples are for illustrative purposes only, and are not intended to limit the invention, and various modifications may be made without departing from the spirit and scope of the invention. Example 1. Compound A-p-Toluenesulfonate and Rosiglitazone Maleate Compound Tablet 12 95021 201219384 Prescription Each tablet contains: Chemical A-p-benzoic acid 50 mg rosiglitazone maleate 4 mg microcrystalline cellulose 10 mg 2% starch slurry appropriate amount of magnesium stearate 0 5 me Preparation method: Compound A p-toluenesulfonate, rosiglitazone maleate, microcrystalline cellulose, mix 2 % starch slurry wet granulation. Dry, add magnesium stearate, and swell on Shanghai. Similarly, a compound such as rosiglitazone or a salt thereof and Compound A or a salt thereof, which are prepared by adjusting the amount of Compound A or a salt thereof, rosiglitazone or a salt thereof in a different ratio, are prepared. The ratio is 1: 6. 25, 1: 12. 5, 1: 25, 1: 50, 1: 75, and so on. Example 2, Compound A, p-Toluenesulfonate and Pioglitazone Hydrochloride Compound Tablets Each tablet contains: Compound A p-toluenesulfonate 5 〇 mg guanglitazone hydrochloride 1.5 mg Microcrystalline cellulose 1 〇 mg 2% starch Appropriate amount of pulp, magnesium stearate. 5mg Preparation method: Compound A p-toluenesulfonate, pioglitazone hydrochloride, microcrystalline cellulose mixed with the use of powder paddle wet granulation. Dry, add magnesium stearate, and mix and compress. Similarly, by adjusting the amount of Compound A or a salt thereof in the compound, pioglitazone or a salt thereof, the ratio of complex J such as gliglitazone or a salt thereof to Compound A or a salt thereof, which is different in the ratio of two active ingredients, is prepared. 7. $ : 95021 13 201219384 25,7. 5 : 50,7. 5 : 75,7. 5 : 100,7. 5 : 150,7· 5 : 375 etc. Test Example 1: In vitro activity and selectivity of Compound A, LAF-237 Method: Thawed DPP-IV - Glo. Buffered and equilibrated to room temperature before use, pre-buffered luciferin detection reagent, suspended DPP-1V — G1 〇. Add ultrapure water to the matrix and mix it gently to make a 1 mM matrix. Place the luciferin detection reagent in a brown bottle and add DPP-1V — G1 〇. The luciferin detection reagent should be dissolved within 1 minute, and the test compound should be dissolved in DMS0 to 50 times the concentration of the test compound. 50 times the concentration of the test compound 2 /z L was added to each tube, and the negative control and blank were added. Add 2 // LDMS0 to the control group, add 46/zL Tris buffer to each tube, add 48 /z LTris buffer to the blank control group, and add 2// to each tube of the negative control and test samples. LDPP4 enzyme, vibrate and centrifuge. The whole material in the test tube was transferred to a 96-well plate, and the ratio of the mixed matrix and DPP-IV-Glo. was 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 30 to 60 minutes before use. Add a mixture of 50 #L DPP-IV-Glo. and matrix to the wells of each 96-well plate, seal the plate with a sealing film, and use a plate shaker. The 96-well material was slowly mixed at 300 to 500 rpm/30 s. Incubation was carried out for 30 minutes to 3 hours at room temperature, and the chemiluminescence count value was measured on a NOVOstar multi-function microplate reader. 14 95021 201219384 [Table 1] Test compound DPP-IV DPP8 DPP9 Ι〇50 (//Μ) Ι〇50 (//Μ) Selection ratio (DPP8/DPP-IV) Ι〇50 (//Μ) Selection ratio (DPP9/DPP-IV) Compound A 0.019 7. 10 374 0.90 47 LAF-237 0.014 3.82 273 0.23 14 Result: The inhibitory activity of Compound A against DPP4 was superior to that of the control drug LAF-237, and the selectivity was also greater than that of LAF-237. Test Example 2: Oral Glycotolerance Study of Different Ratios of Rosiglitazone and Compound A Pharmaceutical Compositions in Normal ICR Mice Male ICR mice were orally administered with double distilled water after 6 hours of fasting, different ratios (rodaglinone horse) Acid salt: Compound A p-toluenesulfonate = 1: 6. 25, 1: 12. 5, 1: 25, 1: 50, 1: 75) The same dose (10 mg / kg) of the pharmaceutical composition, each The group was orally administered with glucose 2.5 g/kg at 30 minutes, and an oral glucose tolerance test was performed. Blood was taken at 0, 30, 60, and 120 minutes after the administration of the sugar, and the serum glucose concentration was measured. Determination of serum glucose; Determination of glucose content in serum by glucose kit, take 250 / 1 enzyme working solution, add 5 / z 1 serum, while setting up a blank tube (add 5 / 1 double distilled water) and standard tube (join 5# 1 glucose standard solution), mix, 37 ° C water for 20 minutes, with a blank tube to zero, OD505r ^ m colorimetric determination. Serum glucose content BG (nraol / l) = 0D sample tube / 0D standard tube x 5. 55 data processing and statistical analysis; 1, using the average SD and Student-t test for statistical analysis of data 15 95021 201219384

2. Calculate the percentage of blood glucose drop and the area under the curve AUC at 30 minutes after the administration of sugar (Table 2): The effect of oral administration of the test drug composition (10 mg/kg) on oral glucose tolerance in normal ICR mice (mean ± SD, n=6) Group weight g Before administration 0 minutes 30 minutes after sugar supply (nmol/1) 60 minutes 120 minutes blank control 27. 5+1.0 6.14±0.86 13. 5+01.48 10.89+1. 88 8.18±0.89 1 : 6.25 25. 0+1.4 6. 26±0. 60 8. 82+2.10** 8. 72+0. 82* 7.17+0.82 1 : 12. 5 27. 2+1. 3 5. 64±0 71 8.15±0.93 木木木 8. 09±0· 67木木 6. 02+0. 23* 1 : 25 28. 2+1.6 6. 32±1.28 8.69±1·12*** 8. 82+ 0. 72* 7.10+0. 53* 1 : 50 27. 8+1. 0 6. 57±0. 64 8·49±1.11 木木木 8. 89+0. 82* 6.61+1.04* 1 : 75 26. 3+3. 7 6. 09+0. 59 8. 44+2. 30** 9. 03+0. 78 7. 28+0. 61 *, P<0. 05; with blank control **, P < 0. 01 ; compared with the blank control group; ***, P < 0. 001; compared with the blank control group; Test Example 3: different ratios of pioglitazone and Compound A pharmaceutical composition to normal Oral glucose tolerance study in ICR mice Male ICR mice were fasted for 6 hours After oral administration of double distilled water, different mixing ratios (pioglitazone hydrochloride: compound A p-toluenesulfonate = 7. 5: ❶ 25, 7. 5: 50, 7.5: 75, 7.5: 100 ' 7. 5: 150, 7.5: 375) A mixture of the same dose (30 mg / kg), each group was orally administered with glucose 2. 5 g / kg for 30 minutes, for oral sugar test. Blood was taken at 0, 30, 60, and 120 minutes after the administration of the sugar, and the serum glucose concentration was measured. Determination of serum glucose; Determination of glucose content in serum by glucose kit, take 250 / 1 enzyme working solution, add 5 / / 1 serum, and set up a blank tube (add 5 16 95021 201219384

# 1 double distilled water) and standard tube (add 5 / / 1 glucose standard solution), mix, 37 ° C water bath for 20 minutes, zero tube with blank tube, colorimetric determination at OD505nm. Serum glucose content BG (nmol / l) = OD sample tube / OD standard tube X 5. 55 data processing and statistical analysis, 1, using the mean soil SD and Student-t test for statistical analysis of data 2, calculated after sugar Percentage of blood glucose drop at 30 minutes and area under the curve AUC [Table 3]: Effect of oral administration of test compound (30 mg/kg) on oral glucose tolerance in normal ICR mice (mean ± SD, r) = 6) Group Weight g before administration of 0 minutes 30 minutes after administration of sugar (nmol / 1) 60 minutes 120 minutes blank control 26. 5 + 1.4 4. 43 ± 0. 72 11.96 ± 1.16 10. 33 + 2.13 6.47 + 1.12 7. 5 : 25 26. 4+0. 5 4. 57±1.20 9. 44+2.14* 7.18+1.33* 5. 73+0. 60 7. 5 : 50 26. 3+1.1 4. 40±0.67 7. 38±1.59 Wood wood 6.13±0· 63** 5. 26±0· 77 7. 5 : 75 26. 2+1.8 4.19+0.77 7. 80+1. 37W 6. 74±0. 87 林 5.16+0. 37 * 7.5:100 26. 0+1.4 3. 92±0. 81 7.11±0.16 木木木6.01+1.13** 5.15+0.71* 7.5:150 25.8+1.7 4.13±1.41 7. 33±2. 22*6 . 02+0. 76«* 5.12+0.66* 7.5:375 26. 5+2. 3 4. 73±0. 80 9. 35±2,19* 8. 33±1.06 6. 68+0. 82 * , Ρ < 0. 05 ; compared with the blank control group; ** , Ρ <0. 01 ; compared with the blank control group; ***, Ρ <0. 001; compared with the blank control group; Test Example 4: the compound Α 曱 曱 sulfonate, LAF-237 and Luo Effect of glitazone maleate or pioglitazone hydrochloride in inherited obese and diabetic Wistar rats 17 95021 201219384 Male Wistar mice aged 14 to 19 weeks were divided into 8 groups of 5 Up to 6 animals, respectively, taking steamed water, Compound A p-toluene hydrochloride, rosiglitazone maleate, η-tiglitazone hydrochloride, LAF-237+ rosiglitazone maleate, LAF-237+°bi-glitazone hydrochloride, compound a-p-benzoate + rosiglitazone maleate and compound A p-toluate + σ-figlitazone hydrochloride for 14 days. Blood was taken from the tail vein, and plasma glucose and hemoglobin A1 were separately determined by enzymatic method using a commercial kit (NC-ROPET, Nippon Chemiphar C0.). The results were expressed as mean standard deviation of each group (n=5 to 6). And analyzed by Dunnett's test, given in Table 4. Use a 1% significance level. [Table 4] Dose of plasma glucose hemoglobin control group 356+31 5. 9+0. 5 5. 9±0. 3~ Compound A p-toluenesulfonate. 1Omg/kg 224±52* Rosiglitazone Acidate 2. 5mg/kg 327+45 J 6· 2+0 6 ° ratio glitazone hydrochloride 5mg/kg 298+27 5.8±〇~ ~TT+〇r~ LAF-237 1Omg/kg 28413Ϊ~ LAF -237+ Rogge yoghurt] Maleate 10mg/kg+2. 5mg/kg 175±13* 4. 7+0. 5* LAF-23 7+Pioglitazone Hydrochloride 10mg/kg+5 mg/kg 168±7* 4. 6±〇. 5氺 Compound A p-Toluenesulfonate + Rosiglitazone Maleate 10mg/kg+2. 5mg/kg 1 A 125±21氺4. 3+0. 4* Compound A p-toluene hydrochloride + 0 glitazone hydrochloride 10 mg/kg + 5 mg/kg 112+17* ^. 4. 2±〇. 3 wood*: Ρ< ο. 〇1 and control Compared with the compound A in Table 4, the combination of toluene sulfonate with rosiglibine bismuth maleate or pioglitazone hydrochloride significantly reduced the concentration of blood glucose and ^ 95021 18 201219384 albumin, the intensity is greater than Compound A p-toluenesulfonate, rosiglitazone maleate, pioglitazone hydrochloride, LAF_237, alone, and its strength is greater than LAF-237 Maleate or pioglitazone pioglitazone hydrochloride in combination. [Simple description of the diagram] M. [Key component symbol description] Helmet

19 95021

Claims (1)

201219384 VII. Patent Application Range: 1. A pharmaceutical composition for treating type 2 diabetes in a mammal, the pharmaceutical composition comprising a therapeutically effective amount of rosiglitazone or σ-by glitazone or a pharmaceutically acceptable salt thereof And (3aS,5s,6aR:)_5_(2 gas (2S, 4S)~2-cyano-4-fluoro-n-pyrrolidine-fluorenyl)-, oxyethylamino)_N,N, 5- Dimercapto-hexahydrocyclopenta[c]pyrrole-2(ih)-guanamine or a pharmaceutically acceptable salt thereof, wherein rosiglitazone or a pharmaceutically acceptable salt thereof (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxoethylamino)-N,N,5-trimethyl_ The weight ratio of hexahydrocyclopenta[c]pyrrole 2(1H)-cartoamine or a pharmaceutically acceptable salt thereof is from 0.25 to 1.75, ° of glitazone or a pharmaceutically acceptable salt thereof (s' 5s,6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-indolyl)-oxoethylamine)·Ν, u-三甲The weight ratio of hexahydrocyclopenta[c> to bismuth-2(10)-carbenamide or a pharmaceutically acceptable salt thereof is 2, wherein the pharmaceutical composition is as described in the patent specification. (2_((2S,(6)""2-cyanofluorine" than 17 calcined; no, ethylamine) - N, N, 5 - tri-tau- 6-cyclopentane [C] oxime than each 2 (1H)-formamide or Its pharmaceutically acceptable amount is 25 to _mg. The parent of the salt is used daily _ or its pharmaceutically acceptable salt = amount = ton 'the pioglitazone or its hydrazine| is from 1 to 12 is 7. H60mg of the above-mentioned acceptable salt per person per week using 95021 20 201219384 4 · Γ: Γ 围 第 第 第 第 第 第 第 第 〜 〜 〜 〜 该 该 该 该 该 该 该 该Capsules, soft capsules, sputum sustained release agents, dropping pills, granules, granules, sustained release micro-ordinary or other oral dosage forms. The pharmaceutical composition described in Item 1-4 of Items 1 to 4勿,,中中(3aS,5s,6aR)_5_(2_((2s,4s)_2_ aryl_4_ 氟-料院+基)-2-ethoxyethylamine)_N. N,5_三甲Base-hexanitrogen The pentyl (6)---methionine or a pharmaceutically acceptable salt thereof is either immediate or slow release. 6. If the scope of the patent is claimed! The pharmaceutical composition of any one of the items 5 to 5, wherein the rosiglitazone or η-tiglitazone or a pharmaceutically acceptable salt thereof is an immediate release or a slow release. 7. If you apply for a patent scope! The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a music composition which is given once a day, twice a day or twice a day. 8• If you apply for a patent scope! The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable salt is selected from the group consisting of p-toluene hydrochloride, sulphate, hydrochloride, sulfate, nitrate, hydrobromide, A Sulfonate, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, besylate, benzoate, naphthalene Acid salt, lactate or malate. A use of the pharmaceutical composition according to any one of claims 1 to 8 for use in the preparation of a medicament for treating diabetes in a mammal including a human. 95021 21 201219384 IV. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (.). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: This case does not represent the chemical formula 95021